The aminobenzyl analog of
propranolol, 1- (p-amino-alpha,alpha-dimethylphenethylamino)-3-(1-naphthoxy)-2-
propanol, was synthesized and found to be a potent
beta-adrenergic blocking agent. The
beta-adrenergic receptors of cultured rat C6
glioma cells (2B clone) as assessed by [(125)I]
iodohydroxybenzylpindolol binding were decreased 50 and >95% after pretreatment with 8 nM and 1 muM aminobenzylpropranolol, respectively. Unlike
propranolol, aminobenzylpropranolol displayed a prolonged blockade of receptors that was maintained during several hours of washing. [(125)I]
Iodohydroxybenzylpindolol saturation binding experiments in cells exposed to aminobenzylpropranolol and subsequently washed indicated that the compound effectively diminished receptor number with no change in the affinity of the remaining receptors for
iodohydroxybenzylpindolol. Aminobenzylpropranolol inhibited
catecholamine-stimulated intracellular
cyclic AMP accumulation; with increasing blockade,
isoproterenol dose-response curves became progressively shifted to the right but the maximal response was unaltered. Aminobenzylpropranolol inhibited the beta-
adrenergic contractile response in atria isolated from rats and guinea pigs. Treatment with 0.1 and 10 muM aminobenzylpropranolol produced decreases of 0.5 and 2 orders of magnitude in the contractile potency of
isoproterenol. As in
glioma cells, aminobenzylpropranolol failed to decrease the maximal response to
isoproterenol. The effects of aminobenzylpropranolol persisted during extensive washing of atria (up to 17 hr). Repeated exposures to
isoproterenol at concentrations sufficient to produce maximal tension development also failed to alleviate the blockade. The inotropic potency of
histamine in guinea pig atria was not affected by aminobenzylpropranolol. These data suggest that
catecholamines are capable of eliciting full
biological responses in
glioma cells and isolated atria even though the great majority of
beta-adrenergic receptors are persistently blocked.